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Journal of the American Academy of... May 2024Perioperative management of antithrombotic agents requires practical and medical considerations. Discontinuing antithrombotic therapies increases the risk of thrombotic... (Review)
Review
Perioperative management of antithrombotic agents requires practical and medical considerations. Discontinuing antithrombotic therapies increases the risk of thrombotic adverse events including cerebrovascular accidents, myocardial infarction, pulmonary embolism, deep vein thrombosis, and retinal artery occlusion. Conversely, continuation of antithrombotic therapy during surgical procedures has associated bleeding risks. Currently, no guidelines exist regarding management of antithrombotic agents in the perioperative period for cutaneous surgeries and practice differs by surgeon. Here, we review the data on antithrombotic medications in patients undergoing cutaneous surgery including medication-specific surgical and postoperative bleeding risk if the medications are continued, and thromboembolic risk if the medications are interrupted. Specifically, we focus on vitamin K antagonist (VKA) (warfarin), direct-acting oral anticoagulants (DOAC) (rivaroxaban, apixaban, edoxaban, dabigatran), antiplatelet medications (aspirin, clopidogrel, prasugrel, ticagrelor, dipyridamole), unfractionated heparin, low molecular weight heparin (enoxaparin and dalteparin), fondaparinux, bruton tyrosine kinase inhibitors (BTKi) (ibrutinib, acalabrutinib), and dietary supplements (i.e., garlic, ginger, gingko).
PubMed: 38735483
DOI: 10.1016/j.jaad.2024.01.096 -
TH Open : Companion Journal To... Jul 2019Direct oral anticoagulants (DOACs) represent an attractive alternative to low-molecular-weight heparins (LMWHs) for the long-term treatment of cancer-associated... (Review)
Review
Direct oral anticoagulants (DOACs) represent an attractive alternative to low-molecular-weight heparins (LMWHs) for the long-term treatment of cancer-associated thrombosis (CT) since they avoid the burden of daily injections. Analyses in subgroups of cancer patients from large randomized trials suggested that DOACs were at least as effective as vitamin K antagonists, while indirect comparisons suggested that DOACs' efficacy and safety profile were comparable to those of LMWHs. In the randomized controlled HOKUSAI-VTE Cancer study, currently the only completed phase III trial on DOACs in CT patients, edoxaban was shown noninferior to dalteparin on the composite primary endpoint of time to first recurrent venous thromboembolism or major bleeding during the 12 months after randomization. Study results suggest that both agents had comparable benefit/risk ratio in patients with CT. Even though this conclusion was valid from a strict statistical viewpoint, it was potentially misleading when interpreting benefit/risk ratios. Besides the obvious heterogeneity of the study population (e.g., 23% of patients no longer had cancer) and significantly different treatment durations between arms, secondary outcomes for efficacy were in favor of edoxaban for recurrent deep-vein thrombosis but not for recurrent pulmonary embolism, and major bleeding episodes were significantly more frequent in the edoxaban group, with an excess of gastrointestinal (GI) bleeding episodes observed mainly but not only in patients with GI cancers. More research is needed regarding specific patients' profiles, cancer types, and treatment period to better clarify the respective roles of DOACs and LMWHs in CT patients.
PubMed: 31535076
DOI: 10.1055/s-0039-1696659 -
Progress in Molecular Biology and... 2019Heparin is an anticoagulant medication that was discovered in 1917 and used in clinic since 1935. Low molecular weight heparins (LMWHs) represent a refined use of... (Review)
Review
Heparin is an anticoagulant medication that was discovered in 1917 and used in clinic since 1935. Low molecular weight heparins (LMWHs) represent a refined use of heparin as anticoagulant medications that were developed in 1980s. LMWHs are obtained by cleaving heparin with different chemical or enzymatic methods. Eight chemically distinct and officially approved LMWHs are Bemiparin, Certoparin, Dalteparin, Enoxaparin, Nadroparin, Parnaparin, Reviparin, and Tinzaparin. LMWHs are mainly used for preventing blood clots, for treating deep vein thrombosis and pulmonary embolism, and for treating myocardial infarction. LMWHs have advantages over heparin in that they can be used at home with good predictability, dose-dependent plasma levels, a long half-life, less bleeding for a given antithrombotic even, smaller risk of osteoporosis in long-term use, and smaller risk of heparin-induced thrombocytopenia and thrombosis, a potential side effect of heparin. However, heparin is reversible with protamine sulfate while LMWHs have no antidote. Moreover, LMWHs have less of an effect on inhibiting thrombin activity than heparin. Furthermore, patients with end-stage renal diseases have to use heparin because LMWHs are dependent on functioning kidney for their clearance but heparin is primarily cleared in the liver. We will review the recent progress made on the clinically approved and under clinical trialed LMWHs and their potential medical applications. In particular, we will provide an update on the chemical characteristics and clinical use of different branded LMWHs. In addition, the potential clinical applications of LMWHs in other therapeutic area will also be discussed.
Topics: Clinical Trials as Topic; Disease; Heparin, Low-Molecular-Weight; Humans
PubMed: 31030749
DOI: 10.1016/bs.pmbts.2019.02.003 -
Expert Review of Hematology Jun 2020Acutely ill and medically complex pediatric patients typically rely on central venous catheters (CVCs) for vascular access. CVCs can have serious complications,... (Review)
Review
INTRODUCTION
Acutely ill and medically complex pediatric patients typically rely on central venous catheters (CVCs) for vascular access. CVCs can have serious complications, including venous thromboembolism (VTE). In children, CVCs are the most common risk factor for VTE.
AREA COVERED
Studies focused on the prevention and treatment of CVC-related VTE in children have been lacking until recently. Currently, there is one U.S. Food and Drug Administration (FDA) approved anticoagulant, dalteparin, and phase 3 trial results for two direct oral anticoagulants (DOACs) in pediatrics have recently been published. This review focuses on the epidemiology, risk factors, prevention, and treatment for CVC-related VTE in children. Data are included from relevant articles in PubMed, 1990 to present.
EXPERT OPINION
With a paucity of FDA-approved anticoagulants for VTE treatment or prophylaxis in children, dosing and monitoring recommendations are often based largely on adult studies. DOACs are a promising group of anticoagulants to be used for children since they are given orally and do not require monitoring. Currently, children at the highest risk for CVC-related VTE are not well represented in the published pediatric DOAC trials.
Topics: Central Venous Catheters; Child; Humans; Risk Factors; Venous Thromboembolism
PubMed: 32290724
DOI: 10.1080/17474086.2020.1756260 -
Ophthalmology Oct 2022Proliferative vitreoretinopathy (PVR) is the major cause for surgical failure after primary rhegmatogenous retinal detachment (RRD). So far, no therapy has been proven... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Proliferative vitreoretinopathy (PVR) is the major cause for surgical failure after primary rhegmatogenous retinal detachment (RRD). So far, no therapy has been proven to prevent PVR. Promising results for 5-fluorouracil (5-FU) and low-molecular weight heparin (LMWH) in high-risk eyes have been reported previously. The objective of this trial was to examine the effect of adjuvant intravitreal therapy with 5-FU and LMWH compared with placebo on incidence of PVR in high-risk patients with primary RRD.
DESIGN
Randomized, double-blind, controlled, multicenter, interventional trial with 1 interim analysis.
PARTICIPANTS
Patients with RRD who were considered to be at high risk for PVR were included. Risk of PVR was assessed by noninvasive aqueous flare measurement using laser flare photometry.
METHODS
Patients were randomized 1:1 to verum (200 mg/ml 5-FU and 5 IU/ml dalteparin) and placebo (balanced salt solution) intravitreally applied during routine pars plana vitrectomy.
MAIN OUTCOME MEASURES
Primary end point was the development of PVR grade CP (full-thickness retinal folds or subretinal strands in clock hours located posterior to equator) 1 or higher within 12 weeks after surgery. For grading, an end point committee assessed fundus photographs. Secondary end points included best-corrected visual acuity and redetachment rate. A group sequential design with 1 interim analysis was applied using the O'Brien and Fleming boundaries. Proliferative vitreoretinopathy grade CP incidence was compared using a Mantel-Haenszel test stratified by surgeon.
RESULTS
A total of 325 patients in 13 German trial sites had been randomized (verum, n = 163; placebo, n = 162). In study eyes, mean laser flare was 31 ± 26 pc/ms. No significant difference was found in PVR rate. Primary analysis in the modified intention-to-treat population results were: verum 28% vs. placebo 23% (including not assessable cases as failures); odds ratio [OR], 1.25; 95% confidence interval [CI], 0.76-2.08; P = 0.77. Those in the per-protocol population were: 12% vs. 12%; OR, 1.05; 95% CI, 0.47-2.34; P = 0.47. None of the secondary end points showed any significant difference between treatment groups. During the study period, no relevant safety risks were identified.
CONCLUSIONS
Rate of PVR did not differ between adjuvant therapy with 5-FU and LMWH and placebo treatment in eyes with RRD.
Topics: Dalteparin; Double-Blind Method; Fluorouracil; Heparin; Heparin, Low-Molecular-Weight; Humans; Retinal Detachment; Vitrectomy; Vitreoretinopathy, Proliferative
PubMed: 35680097
DOI: 10.1016/j.ophtha.2022.05.024 -
Expert Opinion on Biological Therapy Aug 2017The number of people with diabetes mellitus (DM) is estimated to exceed 640 million by the year 2040. Diabetic foot ulcer (DFU) is a debilitating illness that affects... (Review)
Review
The number of people with diabetes mellitus (DM) is estimated to exceed 640 million by the year 2040. Diabetic foot ulcer (DFU) is a debilitating illness that affects more than 2% of DM patients. DFU is caused by DM-induced neural and vascular lesions leading to a reduced sensation and microcirculation. The increase in the prevalence of DFU has prompted researchers to find new therapies for the management of DFU. Areas covered: This review presents the current status of novel biological therapies used in the treatment of DFU. Literature information and data analysis were collected from PubMed, the website of the American Diabetes Association, and ClinicalTrials.gov. The keywords used in the search were: DM, DFU, complications of DM. Expert opinion: Many biological agents have been investigated in a bid to find an effective therapy for DFU. These include growth factors (platelet-derived growth factor, vascular endothelial growth factor etc), stem cells (epithelial progenitor-, adipose-derived stem cells etc), anti-diabetic drugs (insulin, exendin-4), herbs, urokinase, dalteparin, statins and bio-agents such as acid peptide matrix. Biological agents that can reduce hyperglycaemia, increase sensation, microcirculation and oxygenation and repair lost tissue are the most ideal for the treatment of DFU.
Topics: Biological Products; Diabetic Foot; Diabetic Neuropathies; Humans; Hypoglycemic Agents; Immunomodulation; Intercellular Signaling Peptides and Proteins; Stem Cell Transplantation; Urokinase-Type Plasminogen Activator; Wound Healing
PubMed: 28532226
DOI: 10.1080/14712598.2017.1333596 -
Proceedings of the National Academy of... Oct 2022The major cytoskeleton protein actin undergoes cyclic transitions between the monomeric G-form and the filamentous F-form, which drive organelle transport and cell...
The major cytoskeleton protein actin undergoes cyclic transitions between the monomeric G-form and the filamentous F-form, which drive organelle transport and cell motility. This mechanical work is driven by the ATPase activity at the catalytic site in the F-form. For deeper understanding of the actin cellular functions, the reaction mechanism must be elucidated. Here, we show that a single actin molecule is trapped in the F-form by fragmin domain-1 binding and present their crystal structures in the ATP analog-, ADP-Pi-, and ADP-bound forms, at 1.15-Å resolutions. The G-to-F conformational transition shifts the side chains of Gln137 and His161, which relocate four water molecules including W1 (attacking water) and W2 (helping water) to facilitate the hydrolysis. By applying quantum mechanics/molecular mechanics calculations to the structures, we have revealed a consistent and comprehensive reaction path of ATP hydrolysis by the F-form actin. The reaction path consists of four steps: 1) W1 and W2 rotations; 2) P-O bond cleavage; 3) four concomitant events: W1-PO formation, OH and proton cleavage, nucleophilic attack by the OH against P, and the abstracted proton transfer; and 4) proton relocation that stabilizes the ADP-Pi-bound F-form actin. The mechanism explains the slow rate of ATP hydrolysis by actin and the irreversibility of the hydrolysis reaction. While the catalytic strategy of actin ATP hydrolysis is essentially the same as those of motor proteins like myosin, the process after the hydrolysis is distinct and discussed in terms of Pi release, F-form destabilization, and global conformational changes.
Topics: Actins; Adenosine Diphosphate; Adenosine Triphosphate; Dalteparin; Hydrolysis; Myosins; Protons; Water
PubMed: 36252034
DOI: 10.1073/pnas.2122641119 -
La Revue Du Praticien Mar 2022"Treatment of cancer associated thrombosis The treatment of cancer-associated venous thromboembolic disease is complex due to an increased risk of thrombotic recurrence...
"Treatment of cancer associated thrombosis The treatment of cancer-associated venous thromboembolic disease is complex due to an increased risk of thrombotic recurrence and bleeding under treatment. During the first 6 months, low molecular weight heparins are more effective than vitamin k antagonists without increasing the risk of bleeding. Direct oral anticoagulants (doacs) have at least comparable efficacy to delateparin. The hemorrhagic risk of doacs is comparable or higher than that of dalteparin, but seems to depend on the doac studied and, at least for some of them, on the location of the tumor. Beyond the 6th month, the cura-tive anticoagulant treatment is continued as long as the cancer is active with low molecular weight heparin if it is well tolerated and effective or by using a doac at full dose while waiting for the results of a randomized trial comparing the efficacy and safety of half-dose versus full-dose of apixaban."
Topics: Anticoagulants; Humans; Neoplasms; Venous Thromboembolism
PubMed: 35638950
DOI: No ID Found -
Thrombosis and Haemostasis Jul 2024In patients with acute venous thromboembolism (VTE), the rates of recurrence and major bleeding are highest during the first weeks of anticoagulation. The CARAVAGGIO... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
BACKGROUND
In patients with acute venous thromboembolism (VTE), the rates of recurrence and major bleeding are highest during the first weeks of anticoagulation. The CARAVAGGIO trial demonstrated noninferiority of apixaban to dalteparin for treatment of cancer-associated VTE without an increased risk of major bleeding. We compared the early time course of VTE recurrence and major bleeding events of apixaban compared with dalteparin at 7, 30, and 90 days of treatment in patients with cancer-associated VTE.
METHODS
The study design of the CARAVAGGIO trial has been described. Eligible patients were randomly assigned to receive monotherapy with either apixaban or dalteparin for 6 months. The primary efficacy outcome was the incidence of objectively confirmed recurrent VTE. The primary safety outcome was major bleeding.
RESULTS
In 1,155 patients, recurrent VTE after 7, 30, and 90 days occurred in 6 (1%), 15 (2.6%), and 27 (4.7%) patients in the apixaban arm versus 5 (0.9%), 20 (3.5%), and 36 (6.2%) patients respectively in the dalteparin arm. By day 7, 30, and 90, major bleeding events had occurred in 3 (0.5%), 9 (1.6%), and 16 (2.8%) patients in the apixaban group versus 5 (0.9%), 11 (1.9%), and 17 (2.9%) patients in the dalteparin group.
CONCLUSION
The frequencies of recurrent VTE and major bleeding events at 7, 30, and 90 days of apixaban compared with dalteparin were similar in patients with cancer-associated VTE. This supports the use of apixaban for the initiation and early phase of anticoagulant therapy in cancer-associated VTE.
Topics: Humans; Pyridones; Pyrazoles; Dalteparin; Hemorrhage; Neoplasms; Female; Venous Thromboembolism; Male; Middle Aged; Aged; Recurrence; Anticoagulants; Time Factors; Factor Xa Inhibitors; Treatment Outcome; Adult
PubMed: 38196077
DOI: 10.1055/s-0043-1778642 -
European Heart Journal. Cardiovascular... Oct 2019
Topics: Anticoagulants; Blood Coagulation; Clinical Trials as Topic; Dalteparin; Factor Xa Inhibitors; Humans; Neoplasms; Pyridines; Recurrence; Risk Factors; Secondary Prevention; Thiazoles; Treatment Outcome; Venous Thromboembolism
PubMed: 31378809
DOI: 10.1093/ehjcvp/pvz027